Project Summary/Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and impairments in other aspects of cognitive and behavioral function. It is the most common form of dementia, currently afflicting roughly five million Americans, a number projected to quadruple by 2050. Neuropathologically, AD is defined by the accumulation of extracellular plaques composed of beta-amyloid (A?), and intracellular neurofibrillary tangles (NFTs), consisting of phosphorylated forms of the microtubule- associated protein, tau. Mutations in three separate genes have been linked to the rare (<3% of cases), heritable, form of AD. The causes of the far more prevalent, sporadic, form are unknown, though recent work has implicated environmental factors, prominently including stress, as promoting AD pathogenesis. For example, recent epidemiological studies indicate that individuals prone to experience psychological distress or anxiety are at substantially greater risk to develop AD as age-matched controls that score low on this dimension. The overarching hypothesis of this proposal is that chronic stress exposure in humans confers increased risk of AD due to stress-associated alterations in the cortical and hippocampal CRF signaling systems. Based on our preliminary data, we propose that a potential mechanism underlying this stress-AD relationship is the modulation of A? by CRFR1 activation.